Mammalian cell polyamine homeostasis is altered by the radioprotector WR1065.
Mammalian cell polyamine homeostasis is altered by the radioprotector WR1065.
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放射防护剂 WR1065 可改变哺乳动物细胞多胺稳态。
DOI：
10.1042/bj3350329
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Judd,GG
中科院分区：
文献类型：
--
作者：
Mitchell,JL;Rupert,J;Leyser,A;Judd,GG
当哺乳动物细胞天然多胺腐胺、亚精胺和精胺的产生受到限制时，它们更容易受到辐射诱导的死亡和诱变的影响。 N-(2-巯基乙基)-1,3-二氨基丙烷 (WR1065) 可以逆转多胺剥夺的影响，N-(2-巯基乙基)-1,3-二氨基丙烷 (WR1065) 是一种简单的氨基硫醇，因其辐射防护特性已被广泛研究。由于该化合物及其氧化衍生物 WR33278 与多胺有一些相似之处，因此推测 WR1065 或其代谢物的辐射防护作用至少部分源自它们补充天然多胺的能力。为了评估这些氨基硫醇化合物在完整细胞中模拟多胺功能的能力，用辐射防护剂量的 WR1065 处理大鼠肝癌 (HTC) 细胞；监测了该化合物影响正常多胺代谢各个方面的能力。尽管细胞WR1065维持在超过多胺的水平，但这种氨基硫醇对最初的多胺生物合成酶、鸟氨酸脱羧酶或多胺降解反应没有任何多胺样作用。相反，用相对较低水平的WR1065处理导致腐胺和亚精胺合成意外增加。 WR1065 处理增强了鸟氨酸脱羧酶的稳定性，从而提高了其活性。这种稳定性似乎是由于 WR1065 诱导的抗酶合成延迟所致，抗酶是多胺合成和转运的反馈调节所需的关键调节蛋白。 WR1065 诱导的细胞亚精胺增加可能解释了其抗突变特性，但可能不是防止细胞被辐射杀死的因素。这是第一个证据表明可以设计化合物通过靶向调节蛋白抗酶的活性来控制多胺水平。
Mammalian cells become more susceptible to radiation-induced death and mutagenesis when restricted in their production of the natural polyamines putrescine, spermidine and spermine. The effects of polyamine deprivation are reversed byN-(2-mercaptoethyl)-1,3-diaminopropane (WR1065), a simple aminothiol that has been extensively studied for its radioprotectant properties. Because this compound and its oxidized derivative WR33278 bear some resemblance to the polyamines, it was hypothesized that radioprotection by WR1065 or its metabolites is derived, at least in part, from their ability to supplement the natural polyamines. To evaluate the ability of these aminothiol compounds to emulate polyamine function in intact cells, rat liver hepatoma (HTC) cells were treated with radioprotective doses of WR1065; the ability of this compound to affect various aspects of normal polyamine metabolism was monitored. Although cellular WR1065 was maintained at levels exceeding those of the polyamines, this aminothiol did not have any polyamine-like effect on the initial polyamine biosynthetic enzyme, ornithine decarboxylase, or on polyamine degradative reactions. On the contrary, treatment with relatively low levels of WR1065 resulted in an unexpected increase in putrescine and spermidine synthesis. WR1065 treatment enhanced the stability, and consequently the activity, of ornithine decarboxylase. This stabilization seems to result from a WR1065-induced delay in the synthesis of antizyme, a critical regulatory protein required in the feedback modulation of polyamine synthesis and transport. The increase in cellular spermidine induced by WR1065 might explain its antimutagenic properties, but is probably not a factor in protection against cell killing by radiation. This is the first evidence that compounds can be designed to control polyamine levels by targeting the activity of the regulatory protein antizyme.